Pathogenesis, Diagnosis, and Management of Cholangiocarcinoma
TL;DR: A better understanding of the imaging characteristics of iCCAs is gained and advanced cytologic techniques to detect pCCAs are developed, along with advances in classification, diagnosis, and treatment.
About: This article is published in Gastroenterology.The article was published on 2013-12-01 and is currently open access. It has received 930 citations till now.
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TL;DR: The role of these cytokines in important events of carcinogenesis, such as their capacity to generate reactive oxygen and nitrogen species, their potential mutagenic effect, and their involvement in mechanisms for epithelial mesenchymal transition, angiogenesis, and metastasis are explored.
Abstract: Acute inflammation is a response to an alteration induced by a pathogen or a physical or chemical insult, which functions to eliminate the source of the damage and restore homeostasis to the affected tissue. However, chronic inflammation triggers cellular events that can promote malignant transformation of cells and carcinogenesis. Several inflammatory mediators, such as TNF-α, IL-6, TGF-β, and IL-10, have been shown to participate in both the initiation and progression of cancer. In this review, we explore the role of these cytokines in important events of carcinogenesis, such as their capacity to generate reactive oxygen and nitrogen species, their potential mutagenic effect, and their involvement in mechanisms for epithelial mesenchymal transition, angiogenesis, and metastasis. Finally, we will provide an in-depth analysis of the participation of these cytokines in two types of cancer attributable to chronic inflammatory disease: colitis-associated colorectal cancer and cholangiocarcinoma.
1,311 citations
Cites background from "Pathogenesis, Diagnosis, and Manage..."
...Researchers have since identified several substances that can be produced by CCAassociated fibroblasts, including periostin, hepatocyte growth factor (HGF), tenascin-C, and CXCL-12 [243, 244]....
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TL;DR: Advances in comprehensive whole-exome and transcriptome sequencing have defined the genetic landscape of each cholangiocarcinoma subtype, and promising molecular targets for precision medicine have been identified, and are being evaluated in clinical trials, including those exploring immunotherapy.
Abstract: Cholangiocarcinoma is a disease entity comprising diverse epithelial tumours with features of cholangiocyte differentiation: cholangiocarcinomas are categorized according to anatomical location as intrahepatic (iCCA), perihilar (pCCA), or distal (dCCA). Each subtype has a distinct epidemiology, biology, prognosis, and strategy for clinical management. The incidence of cholangiocarcinoma, particularly iCCA, has increased globally over the past few decades. Surgical resection remains the mainstay of potentially curative treatment for all three disease subtypes, whereas liver transplantation after neoadjuvant chemoradiation is restricted to a subset of patients with early stage pCCA. For patients with advanced-stage or unresectable disease, locoregional and systemic chemotherapeutics are the primary treatment options. Improvements in external-beam radiation therapy have facilitated the treatment of cholangiocarcinoma. Moreover, advances in comprehensive whole-exome and transcriptome sequencing have defined the genetic landscape of each cholangiocarcinoma subtype. Accordingly, promising molecular targets for precision medicine have been identified, and are being evaluated in clinical trials, including those exploring immunotherapy. Biomarker-driven trials, in which patients are stratified according to anatomical cholangiocarcinoma subtype and genetic aberrations, will be essential in the development of targeted therapies. Targeting the rich tumour stroma of cholangiocarcinoma in conjunction with targeted therapies might also be useful. Herein, we review the evolving developments in the epidemiology, pathogenesis, and management of cholangiocarcinoma.
913 citations
Sapienza University of Rome1, Marche Polytechnic University2, University of Copenhagen3, University of Milan4, Rikshospitalet–Radiumhospitalet5, University of Oslo6, University of Edinburgh7, University of Würzburg8, Greifswald University Hospital9, University of Zurich10, Medical University of Vienna11, University of Salamanca12
TL;DR: This Consensus Statement aims to provide valuable information on classifications, pathological features, risk factors, cells of origin, genetic and epigenetic modifications and current therapies available for this cancer.
Abstract: Cholangiocarcinoma (CCA) is a heterogeneous group of malignancies with features of biliary tract differentiation. CCA is the second most common primary liver tumour and the incidence is increasing worldwide. CCA has high mortality owing to its aggressiveness, late diagnosis and refractory nature. In May 2015, the "European Network for the Study of Cholangiocarcinoma" (ENS-CCA: www.enscca.org or www.cholangiocarcinoma.eu) was created to promote and boost international research collaboration on the study of CCA at basic, translational and clinical level. In this Consensus Statement, we aim to provide valuable information on classifications, pathological features, risk factors, cells of origin, genetic and epigenetic modifications and current therapies available for this cancer. Moreover, future directions on basic and clinical investigations and plans for the ENS-CCA are highlighted.
904 citations
TL;DR: The subgroup with the poorest prognosis had significant enrichment of hypermutated tumors and a characteristic elevation in the expression of immune checkpoint molecules, suggesting immune-modulating therapies might also be potentially promising options for these patients.
Abstract: The incidence of biliary tract cancer (BTC), including intrahepatic (ICC) and extrahepatic (ECC) cholangiocarcinoma and gallbladder cancer, has increased globally; however, no effective targeted molecular therapies have been approved at the present time. Here we molecularly characterized 260 BTCs and uncovered spectra of genomic alterations that included new potential therapeutic targets. Gradient spectra of mutational signatures with a higher burden of the APOBEC-associated mutation signature were observed in gallbladder cancer and ECC. Thirty-two significantly altered genes, including ELF3, were identified, and nearly 40% of cases harbored targetable genetic alterations. Gene fusions involving FGFR2 and PRKACA or PRKACB preferentially occurred in ICC and ECC, respectively, and the subtype-associated prevalence of actionable growth factor-mediated signals was noteworthy. The subgroup with the poorest prognosis had significant enrichment of hypermutated tumors and a characteristic elevation in the expression of immune checkpoint molecules. Accordingly, immune-modulating therapies might also be potentially promising options for these patients.
840 citations
Memorial Sloan Kettering Cancer Center1, Cornell University2, University of Michigan3, Institut Gustave Roussy4, University of Verona5, University of Kansas6, Baylor University Medical Center7, Mayo Clinic8, Memorial Hospital of South Bend9, Johns Hopkins University School of Medicine10, Seoul National University Hospital11, Fox Chase Cancer Center12, University of Chicago13, Katholieke Universiteit Leuven14, Incyte15, Hannover Medical School16
TL;DR: These data support the therapeutic potential of pemigatinib in previously treated patients with cholangiocarcinoma who have FGFR2 fusions or rearrangements.
Abstract: Summary Background Fibroblast growth factor receptor (FGFR) 2 gene alterations are involved in the pathogenesis of cholangiocarcinoma. Pemigatinib is a selective, potent, oral inhibitor of FGFR1, 2, and 3. This study evaluated the safety and antitumour activity of pemigatinib in patients with previously treated, locally advanced or metastatic cholangiocarcinoma with and without FGFR2 fusions or rearrangements. Methods In this multicentre, open-label, single-arm, multicohort, phase 2 study (FIGHT-202), patients aged 18 years or older with disease progression following at least one previous treatment and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 recruited from 146 academic or community-based sites in the USA, Europe, the Middle East, and Asia were assigned to one of three cohorts: patients with FGFR2 fusions or rearrangements, patients with other FGF/FGFR alterations, or patients with no FGF/FGFR alterations. All enrolled patients received a starting dose of 13·5 mg oral pemigatinib once daily (21-day cycle; 2 weeks on, 1 week off) until disease progression, unacceptable toxicity, withdrawal of consent, or physician decision. The primary endpoint was the proportion of patients who achieved an objective response among those with FGFR2 fusions or rearrangements, assessed centrally in all patients who received at least one dose of pemigatinib. This study is registered with ClinicalTrials.gov , NCT02924376 , and enrolment is completed. Findings Between Jan 17, 2017, and March 22, 2019, 146 patients were enrolled: 107 with FGFR2 fusions or rearrangements, 20 with other FGF/FGFR alterations, 18 with no FGF/FGFR alterations, and one with an undetermined FGF/FGFR alteration. The median follow-up was 17·8 months (IQR 11·6–21·3). 38 (35·5% [95% CI 26·5–45·4]) patients with FGFR2 fusions or rearrangements achieved an objective response (three complete responses and 35 partial responses). Overall, hyperphosphataemia was the most common all-grade adverse event irrespective of cause (88 [60%] of 146 patients). 93 (64%) patients had a grade 3 or worse adverse event (irrespective of cause); the most frequent were hypophosphataemia (18 [12%]), arthralgia (nine [6%]), stomatitis (eight [5%]), hyponatraemia (eight [5%]), abdominal pain (seven [5%]), and fatigue (seven [5%]). 65 (45%) patients had serious adverse events; the most frequent were abdominal pain (seven [5%]), pyrexia (seven [5%]), cholangitis (five [3%]), and pleural effusion (five [3%]). Overall, 71 (49%) patients died during the study, most frequently because of disease progression (61 [42%]); no deaths were deemed to be treatment related. Interpretation These data support the therapeutic potential of pemigatinib in previously treated patients with cholangiocarcinoma who have FGFR2 fusions or rearrangements. Funding Incyte Corporation.
756 citations
References
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TL;DR: Fibroblasts are a key determinant in the malignant progression of cancer and represent an important target for cancer therapies.
Abstract: Tumours are known as wounds that do not heal - this implies that cells that are involved in angiogenesis and the response to injury, such as endothelial cells and fibroblasts, have a prominent role in the progression, growth and spread of cancers. Fibroblasts are associated with cancer cells at all stages of cancer progression, and their structural and functional contributions to this process are beginning to emerge. Their production of growth factors, chemokines and extracellular matrix facilitates the angiogenic recruitment of endothelial cells and pericytes. Fibroblasts are therefore a key determinant in the malignant progression of cancer and represent an important target for cancer therapies.
4,232 citations
"Pathogenesis, Diagnosis, and Manage..." refers background in this paper
...The tumor stroma surrounds the malignant ducts and glands and comprises most of the tumor mass.(92,93) The stroma promotes tumor progression via reciprocal communication between the stromal cells and cancer cells....
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...However, the importance of the desmoplastic stroma in CCA progression indicates that it could be a new therapeutic target, perhaps via selective targeting of CAFs.110 Animal Models Animal models are essential for the development of new therapeutic strategies and diagnostic tools.111 Animal models of CCA (Table 1) include mice with xenograft tumors,43,112–119 mice with genetic changes that lead to CCA formation,86,120–124 rats with orthotopic tumors,125,126 and animals that develop CCAs after exposure to carcinogens.55,127–129 Although these models offer an opportunity to bridge the chasm between in vitro findings and clinical applicability, they have limitations....
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...The tumor stroma surrounds the malignant ducts and glands and comprises most of the tumor mass.92,93 The stroma promotes tumor progression via reciprocal communication between the stromal cells and cancer cells.92 The precise origin of CAFs is unclear, although several cell types, including hepatic stellate cells, portal fibroblasts, and bone marrow–derived precursor cells, have been proposed as candidates.92,94–96 The EMT also has been proposed to produce CAFs.93 During tumorigenesis, the EMT is characterized by the presence of tumor cells that express mesenchymal markers such as vimentin, tenascin, fibronectin, and the zinc finger protein Snail.92 Immunohistochemical studies have shown the expression of these markers by human CCA cell lines.97–99 In mice, xenograft tumors grown from enhanced green fluorescent protein (EGFP)-expressing human CCA cells were found to be surrounded and infiltrated by a-SMA–expressing CAFs....
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...The EMT also has been proposed to produce CAFs.(93) During tumorigenesis, the EMT is characterized by the presence of tumor cells that express mesenchymal markers such as vimentin, tenascin, fibronectin, and the zinc finger protein Snail....
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TL;DR: Cisplatin plus gemcitabine is an appropriate option for the treatment of patients with advanced biliary cancer and was associated with a significant survival advantage without the addition of substantial toxicity.
Abstract: Background There is no established standard chemotherapy for patients with locally advanced or metastatic biliary tract cancer. We initially conducted a randomized, phase 2 study involving 86 patients to compare cisplatin plus gemcitabine with gemcitabine alone. After we found an improvement in progression-free survival, the trial was extended to the phase 3 trial reported here. Methods We randomly assigned 410 patients with locally advanced or metastatic cholangiocarcinoma, gallbladder cancer, or ampullary cancer to receive either cisplatin (25 mg per square meter of body-surface area) followed by gemcitabine (1000 mg per square meter), each administered on days 1 and 8, every 3 weeks for eight cycles, or gemcitabine alone (1000 mg per square meter on days 1, 8, and 15, every 4 weeks for six cycles) for up to 24 weeks. The primary end point was overall survival. Results After a median follow-up of 8.2 months and 327 deaths, the median overall survival was 11.7 months among the 204 patients in the cisplat...
3,069 citations
"Pathogenesis, Diagnosis, and Manage..." refers background in this paper
...The standard practice of care for advanced-stage iCCA is systemic chemotherapy with gemcitabine and cisplatin.(141)...
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TL;DR: The dynamic tumour topography varies drastically even throughout the same lesion, so evaluating tumours as complete organs, and not simply as masses of transformed epithelial cells, becomes paramount.
Abstract: Tumour formation involves the co-evolution of neoplastic cells together with extracellular matrix, tumour vasculature and immune cells Successful outgrowth of tumours and eventual metastasis is not determined solely by genetic alterations in tumour cells, but also by the fitness advantage such mutations confer in a given environment As fitness is context dependent, evaluating tumours as complete organs, and not simply as masses of transformed epithelial cells, becomes paramount The dynamic tumour topography varies drastically even throughout the same lesion Heterologous cell types within tumours can actively influence therapeutic response and shape resistance
2,020 citations
"Pathogenesis, Diagnosis, and Manage..." refers background in this paper
...Carcinogenesis in CCA includes alterations in the stroma, recruitment of fibroblasts, remodeling of the extracellular matrix (ECM), changing patterns of immune cell migration, and promotion of angiogenesis (Figure 3A).(91) iCCAs and pCCAs are characterized by a dense and reactive desmoplastic stroma (Figure 3B) that contains many a-smooth muscle actin (a-SMA)–positive myofibroblasts, also known as cancer-associated fibroblasts (CAFs)....
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01 Jan 2011
1,119 citations
TL;DR: Some data point to a potential role for chronic liver disease, hepatitis C, and probably hepatitis B infections in the development of ICC, as well as the recent increasing trends of ICC in the United States.
Abstract: The incidence rates of cholangiocarcinoma (CC) vary greatly among different areas of the world, and this variation is related to distribution of risk factors. Intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC) have different epidemiological features. Recent data show that the incidence and mortality rates of ICC have been increasing in several areas around the world. On the other hand, the incidence and mortality rates of ECC have been decreasing. For example, in the United States, the age-adjusted incidence rates of ICC increased by 165% from 0.32 per 100,000 in 1975 to 1979 to 0.85 per 100,000 in 1995 to 1999, whereas ECC declined by 14%. In the meantime, there has been very little improvement in long-term survival, which remains dismal (3.5%). Men are affected 1.5 times more than women are, and Asians are affected almost 2 times more than whites and blacks. There are few well-established risk factors for CC, including primary sclerosing cholangitis, liver fluke infestations, hepatolithiasis, Thorotrast exposure, and choledochal cysts. None of these risk factors can explain the recent increasing trends of ICC in the United States. Some data, however, point to a potential role for chronic liver disease, hepatitis C, and probably hepatitis B infections in the development of ICC.
1,098 citations
"Pathogenesis, Diagnosis, and Manage..." refers background in this paper
...1 per 100,000 in Australia.(9,10) Differences in the prevalence of genetic and other risk factors presumably account for this extensive variation....
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...The global incidence of iCCA varies widely, from rates of 113 per 100,000 in Thailand to 0.1 per 100,000 in Australia.9,10 Differences in the prevalence of genetic and other risk factors presumably account for this extensive variation....
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